Intestinal motility responses to neuropeptide γ in vitro and in vivo in the rat: comparison with neurokinin 1 and neurokinin 2 receptor agonists

We have studied the effect of a novel tachykinin, neuropeptide γ(NPγ) on small intestinal motility in the rat. Experiments were done in vitro on longitudinal muscle strips of duodenum, and in vivo on the migrating myoelectric complex (MMC) of the small intestine. In vitro, contractile effects of NPγ were compared with those of a selective neurokinin 1 (NK1) receptor agonist, substance P methyl ester (SPME), and a selective neurokinin 2 (NK2) receptor agonist, Nle¹⁰-NKA(4–10)(NleNKA). NPγ, SPME and NleNKA caused concentration-dependent contractions (P < 0.001). NPγ was eight-fold more potent than NleNKA, and 118-fold more potent than SPME. Contractile responses to NPγ were reduced by hexamethonium (P < 0.01) and atropine (P < 0.05). The non-selective NK receptor antagonist spantide I only slightly reduced the contractile response to NPγ, as did the selective NK1 antagonist GR 82334, and the selective NK2 antagonist L-659877 and MEN 10376. In vivo, effects of NPγ on the MMC were compared with those of the natural tachykinins substance P (SP) and neurokinin A (NKA). NPy disrupted the MMC and induced irregular spiking in a dose-dependent manner from 25 to 100 pmol kg^-1 min^-1 i.v. (P < 0.05). The effect of NPγ was more prominent than that of NKA at equal doses, while SP had no effect. Our findings show that NPγ exerts potent stimulatory effects on small intestinal motility, most likely mediated directly via distinct NK receptors on smooth muscle cells, but also indirectly via a cholinergic link.